Management of Crohn Disease: A Review Cushing, Kelly; Higgins, Peter D. R
JAMA : the journal of the American Medical Association,
01/2021, Letnik:
325, Številka:
1
Journal Article
Recenzirano
IMPORTANCE: Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term ...complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance. OBSERVATIONS: The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti–tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy. CONCLUSIONS AND RELEVANCE: The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.
In this trial involving patients at increased risk for pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP), rectal indomethacin reduced the incidence of this condition, as ...compared with placebo (9% vs. 17%).
Acute pancreatitis is the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP),
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accounting for substantial morbidity, occasional death, and estimated health care expenditures of approximately $150 million annually in the United States.
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,
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Given the magnitude of this problem, more than 35 pharmacologic agents have been studied for the prophylaxis of post-ERCP pancreatitis, and many prospective clinical trials addressing chemoprevention have been conducted. To date, however, no medication has proved to be consistently effective in preventing post-ERCP pancreatitis on the basis of data from high-quality clinical trials, and no pharmacologic prophylaxis for post-ERCP pancreatitis is in widespread clinical use. . . .
Abstract
Patients with inflammatory bowel disease (IBD) are at significantly increased risk of colorectal cancer (CRC), principally resulting from the pro-neoplastic effects of chronic intestinal ...inflammation. Epidemiologic studies continue to highlight the increased risk of CRC in IBD. However, the incidence has declined over the past 30 years, attributed to both successful CRC-surveillance programs and improved control of mucosal inflammation. Risk factors that further increase the risk of IBD-related CRC include disease duration, extent and severity, the presence of inflammatory pseudopolyps, coexistent primary sclerosing cholangitis, and a family history of CRC. All major professional societies agree that IBD-CRC surveillance should occur more frequently than in the general population. Yet, guidelines and consensus statements differ on the surveillance schedule and preferred method of surveillance. Improved sensitivity to previously “invisible” flat dysplastic lesions using high definition and chromoendoscopy methods has resulted in many guidelines abandoning requirements for random untargeted biopsies of the colon. While colonic dysplasia remains a worrisome finding, and several clinical scenarios remain best addressed by total proctocolectomy due to concerns of synchronous undetected lesions and the unpredictable tempo of progression to malignancy, better detection techniques have also increased opportunities for endoscopic resection of dysplastic lesions that can be clearly delineated. Finally, the expanding armamentarium of medical options in IBD, including anti-tumor necrosis factor and anti-adhesion biologic therapies, have substantially improved our ability to control severe inflammation and likely reduce the risk of CRC over time.
Corticosteroids are effective for the short-term treatment of inflammatory bowel disease (IBD). Long-term use, however, is associated with significant adverse effects. To define the: (1) frequency ...and duration of corticosteroid use, (2) frequency of escalation to corticosteroid-sparing therapy, (3) rate of complications related to corticosteroid use, (4) rate of appropriate bone density measurements (dual energy X-ray absorptiometry DEXA scans), and (5) factors associated with escalation and DEXA scans.
Retrospective review of Veterans Health Administration (VHA) data from 2002-2010.
Of the 30,456 Veterans with IBD, 32% required at least one course of corticosteroids during the study time period, and 17% of the steroid users had a prolonged course. Among these patients, only 26.2% underwent escalation of therapy. Patients visiting a gastroenterology (GI) physician were significantly more likely to receive corticosteroid-sparing medications. Factors associated with corticosteroid-sparing medications included younger age (OR = 0.96 per year,95%CI:0.95, 0.97), male gender (OR = 2.00,95%CI:1.16,3.46), GI visit during the corticosteroid evaluation period (OR = 8.01,95%CI:5.85,10.95) and the use of continuous corticosteroids vs. intermittent corticosteroids (OR = 2.28,95%CI:1.33,3.90). Rates of complications per 1000 person-years after IBD diagnosis were higher among corticosteroid users (venous thromboembolism VTE 9.0%; fragility fracture 2.6%; Infections 54.3) than non-corticosteroid users (VTE 4.9%; fragility fracture 1.9%; Infections 26.9). DEXA scan utilization rates among corticosteroid users were only 7.8%.
Prolonged corticosteroid therapy for the treatment of IBD is common and is associated with significant harm to patients. Patients with prolonged use of corticosteroids for IBD should be referred to gastroenterology early and universal efforts to improve the delivery of high quality care should be undertaken.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Crohn's disease is often purely inflammatory at presentation, but most patients develop strictures and fistulae over time (complicated disease). Many studies have suggested that nucleotide-binding ...oligomerization domain 2 (NOD2) mutations are associated with a varying but increased risk of complicated disease. An accurate and sufficiently powerful predictor of complicated disease could justify the early use of biological therapy in high-risk individuals. We performed a systematic review and meta-analysis to obtain accurate estimates of the predictive power of the identified mutations (such as p.R702W, P.G908R, and p.Leu1007fsX1008) in NOD2 for the risk of complicated disease.
An electronic search of MEDLINE, Embase, and Web of Science identified 917 relevant papers. Inclusion required specification of genetic mutations at the individual level and disease phenotypes by Vienna classification (inflammatory (B1), stricturing (B2), and fistulizing (B3)). A total of 49 studies met these criteria, which included 8,893 subjects, 2,897 of whom had NOD2 mutations. Studies were weighted by median disease duration. Studies not providing duration data were weighted at the level of the study with the shortest disease duration (3.9 years).
The relative risk (RR) of the presence of any NOD2 mutant allele for complicated disease (B2 or B3) was 1.17 (95% confidence interval (95% CI) 1.10-1.24; P<0.001). P.G908R was associated with an RR of complicated disease of 1.33 (95% CI 1.11-1.60; P=0.002). NOD2 did not predict perianal disease (P=0.4). The RR of surgery was 1.58 (95% CI 1.38-1.80; P<0.001). There was substantial heterogeneity across all studies (I(2)=66.7%). On the basis of logistic regression of these data, the sensitivity of any mutation in predicting complicated disease was 36% and specificity was 73%, with the area under the receiver operating characteristic curve 0.56.
The presence of a single NOD2 mutation predicted an 8% increase in the risk for complicated disease (B2 or B3), and a 41% increase with 2 mutations. Surgery risk is increased by 58% with any NOD2 mutation, whereas perianal disease was unchanged. The predictive power associated with a single NOD2 mutation is weak. The RR of any NOD2 mutations for complicated disease was only 17% across 36 studies. However, the presence of two NOD2 mutations had 98% specificity for complicated disease. These data provide insufficient evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, if prospective trials can demonstrate changes in the natural history in this subset of patients.
Data on external validation of models developed to distinguish Crohn's disease (CD) from intestinal tuberculosis (ITB) are limited. This study aimed to validate and compare models using clinical, ...endoscopic, and/or pathology findings to differentiate CD from ITB.
Data from newly diagnosed ITB and CD patients were retrospectively collected from 5 centers located in Thailand or Hong Kong. The data was applied to Lee, et al., Makharia, et al., Jung, et al., and Limsrivilai, et al. model.
Five hundred and thirty patients (383 CD, 147 ITB) with clinical and endoscopic data were included. The area under the receiver operating characteristic curve (AUROC) of Limsrivilai's clinical-endoscopy (CE) model was 0.853, which was comparable to the value of 0.862 in Jung's model (p = 0.52). Both models performed significantly better than Lee's endoscopy model (AUROC: 0.713, p<0.01). Pathology was available for review in 199 patients (116 CD, 83 ITB). When 3 modalities were combined, Limsrivilai's clinical-endoscopy-pathology (CEP) model performed significantly better (AUROC: 0.887) than Limsrivilai's CE model (AUROC: 0.824, p = 0.01), Jung's model (AUROC: 0.798, p = 0.005) and Makharia's model (AUROC: 0.637, p<0.01). In 83 ITB patients, the rate of misdiagnosis with CD when used the proposed cutoff values in each original study was 9.6% for Limsrivilai's CEP, 15.7% for Jung's, and 66.3% for Makharia's model.
Scoring systems with more parameters and diagnostic modalities performed better; however, application to clinical practice is still limited owing to high rate of misdiagnosis of ITB as CD. Models integrating more modalities such as imaging and serological tests are needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Predictive models for hepatocellular carcinoma (HCC) have been limited by modest accuracy and lack of validation. Machine-learning algorithms offer a novel methodology, which may improve HCC risk ...prognostication among patients with cirrhosis. Our study's aim was to develop and compare predictive models for HCC development among cirrhotic patients, using conventional regression analysis and machine-learning algorithms.
We enrolled 442 patients with Child A or B cirrhosis at the University of Michigan between January 2004 and September 2006 (UM cohort) and prospectively followed them until HCC development, liver transplantation, death, or study termination. Regression analysis and machine-learning algorithms were used to construct predictive models for HCC development, which were tested on an independent validation cohort from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. Both models were also compared with the previously published HALT-C model. Discrimination was assessed using receiver operating characteristic curve analysis, and diagnostic accuracy was assessed with net reclassification improvement and integrated discrimination improvement statistics.
After a median follow-up of 3.5 years, 41 patients developed HCC. The UM regression model had a c-statistic of 0.61 (95% confidence interval (CI) 0.56-0.67), whereas the machine-learning algorithm had a c-statistic of 0.64 (95% CI 0.60-0.69) in the validation cohort. The HALT-C model had a c-statistic of 0.60 (95% CI 0.50-0.70) in the validation cohort and was outperformed by the machine-learning algorithm. The machine-learning algorithm had significantly better diagnostic accuracy as assessed by net reclassification improvement (P<0.001) and integrated discrimination improvement (P=0.04).
Machine-learning algorithms improve the accuracy of risk stratifying patients with cirrhosis and can be used to accurately identify patients at high-risk for developing HCC.
Irritable bowel syndrome (IBS) is a common gastrointestinal condition with a heterogeneous pathophysiology. An altered gut microbiome has been identified in some IBS patients, and fecal microbiota ...transplantation (FMT) has been suggested to treat IBS. We performed meta-analyses and systematic review of available randomized controlled trials (RCTs) to evaluate the efficacy of FMT in IBS.
We performed a systematic literature search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. Selection criteria included RCTs of FMT vs placebo using FMT excipients or autologous FMT in IBS. Meta-analyses were conducted to evaluate the summary relative risk (RR) and 95% confidence intervals (CIs) of combined studies for primary outcome of improvement in global IBS symptoms as measured by accepted integrative symptom questionnaires or dichotomous responses to questions of overall symptom improvement.
Among 742 citations identified, 7 were deemed to be potentially relevant, of which 4 studies involving 254 participants met eligibility. No significant difference in global improvement of IBS symptoms was observed at 12 weeks in FMT vs placebo (RR = 0.93; 95% CI 0.48-1.79). Heterogeneity among studies was significant (I = 79%). Subgroup analyses revealed benefits of single-dose FMT using colonoscopy and nasojejunal tubes in comparison with autologous FMT for placebo treatment (number needed to treat = 5, RR = 1.59; 95% CI 1.06-2.39; I = 0%) and a reduction in likelihood of improvement of multiple-dose capsule FMT RCTs (number needed to harm = 3, RR = 0.54; 95% CI 0.34-0.85; I = 13%). Placebo response was 33.7% in nonoral FMT RCTs and 67.8% in capsule FMT RCTs. The Grading of Recommendations Assessment, Development and Evaluation quality of the body of evidence was very low.
Current evidence from RCTs does not suggest a benefit of FMT for global IBS symptoms. There remain questions regarding the efficacy of FMT in IBS as well as the lack of a clean explanation on the discrepant results among RCTs in subgroup analyses.
Statins and cancer prevention Lippman, Scott M; Demierre, Marie-France; Higgins, Peter D. R ...
Nature reviews. Cancer,
200512, 2005-Dec, 2005-12-00, 20051201, Letnik:
5, Številka:
12
Journal Article
Recenzirano
Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led ...to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Recent treatment guidelines recommend two first-line therapies for Helicobacter pylori infection: proton pump inhibitor (PPI), bismuth, tetracycline, and metronidazole (quadruple therapy) or PPI, ...clarithromycin, and amoxicillin (triple therapy). We performed a systematic review and meta-analysis to compare the efficacy and tolerability of these regimens as first-line treatment of H. pylori.
A search of MEDLINE, EMBASE, Google Scholar, the Cochrane Central Register of Controlled Trials, ACP Journal Club, the Database of Abstracts of Reviews of Effectiveness, Cochrane Methodology Register, Health Technology Assessment Database, and abstracts from prominent gastrointestinal scientific meetings was carried out. Randomized controlled trials (RCTs) comparing bismuth quadruple therapy to clarithromycin triple therapy were selected for meta-analysis. Two independent reviewers extracted data, using standardized data forms. Meta-analysis was carried out with the metan command in Stata 10.1. Funnel plots and subgroup analyses were carried out.
Nine RCTs (N=1,679) were included. Although dosing regimens of clarithromycin triple therapy were quite consistent between trials, dosing regimens varied considerably for bismuth quadruple therapy. Bismuth quadruple therapy achieved eradication in 78.3% of patients, whereas clarithromycin triple therapy achieved an eradication rate of 77.0% (risk ratio (RR)=1.002, 95% confidence interval (CI): 0.936-1.073). There was moderate heterogeneity and no evidence for significant publication bias. Subgroup analyses by study location, treatment duration, and study population did not account for the heterogeneity. There were no statistically significant differences in side effects yielded by quadruple vs. clarithromycin triple therapy (RR=1.04, 95% CI: 1.04-1.14).
Quadruple and triple therapies yielded similar eradication rates as primary therapy for H. pylori infection. Both therapies yielded suboptimal eradication rates. Patient compliance and side effects are similar for quadruple and triple therapies.
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